Synthesis and evaluation of Quinoline-3-carbonitrile derivatives as potential antibacterial agents

Abstract

New quinoline-3-carbonitrile derivatives were synthesized and evaluated for their potential antibacterial behavior. Compounds were obtained by a one-pot multicomponent reaction of appropriate aldehyde, ethyl cyanoacetate, 6-methoxy-1,2,3,4-tetrahydro-naphthalin-1-one and ammonium acetate. Structures were established by different physical and spectroscopic techniques. The molecular geometry, vibration frequencies, HOMO–LUMO energy gap, molecular hardness (g), ionization energy (IE), electron affinity (EA), and total energy of these compounds was assessed by DFT studies, employing DFT/RB3LYP method. Preliminary antibacterial studies using both Gram-positive and Gram-negative bacterial strains and cytotoxicity studies on mammalian cells revealed their promising antibacterial activity, without causing any severe host toxicity. All the compounds (QD1-QD5) in this study obeyed the ‘Lipinski’s Rule of Five’ with logP values <5 and HBA <10, hydrogen bond donor’s <5. The most active compound QD4 showed good interaction with the target DNA gyrase; target enzyme for quinoline class of antibiotics, which reveals its probable mechanism of action. Results of all these studies establish these compounds as important scaffolds with broad-spectrum antibacterial activity with no off-target toxicity. Having lower band gap energy of 3.40 eV and a low lying LUMO for compound QD4, this compound may be a valuable starting point for the development of quinoline-3-carbonitrile based broad-spectrum antibacterial agents.